Preparing pyrazolopyrimidinone derivatives for the treatment of impotence

ABSTRACT

The present invention relates to the method for preparing pyrazolopyrimidinone derivatives and their pharmaceutically acceptable salts having efficacy on the treatment of impotence, one of male sexual dysfunctions. The method according to the present invention comprises the steps of chlorosufonation the pyrazolamide, followed by amination with amine and intramolecular cyclization. The method provides the pyrazolopyrimidinone derivatives and their pharmaceutically acceptable salts with high yield and in an economic manner.

TECHNICAL FIELD

[0001] The present invention relates to a process for preparingpyrazolopyrimidinone derivatives of formula 1 and pharmaceuticallyacceptable salts thereof which have an efficacy on impotence, comprisingthe steps of chlorosulfonation of pyrazolamide compounds of formula 2,followed by amination with a primary amine and intramolecularcyclization.

[0002] The compounds of formula 1 may exist in tautomeric equilibrium asshown below.

[0003] The compounds of formula 1 may also contain asymmetric centersand thus they can exist as enantiomers. The present invention includesboth racemic mixture and separate individual enantiomers.

BACKGROUND ART OF THE INVENTION

[0004] Male erectile dysfunction is one of the most common sexualdysfunctions in man. Although erectile dysfunction can be primarilypsychogenic in origin, it often accompanies chronic illnesses, such asdiabetes mellitus, heart disease and a variety of neurological diseases.It is estimated that about 2˜7% of the male population are impotent. Itsprevalence is strongly related to age. For example, 18˜75% of the agegroup of 55 to 80 years is believed to be impotent.

[0005] Various treatment options for erectile dysfunction are available,such as counseling, hormone replacement therapy, self-injection ortransurethral application of vasodilator agents, vacuum devices, andvascular surgery. However, these therapeutic options have severallimitations such as side effects, high cost and low efficacy.

[0006] Recently, Sildenafil has been developed as a therapeutic agentfor male erectile dysfuction by oral administration. Sildenafil is thefirst in a new class of drugs known as inhibiting phosphodiesterase-5enzyme distributed specifically in corpus cavernosal tissues and inducesrelaxation of the corpus cavernosal smooth muscle cells, so that bloodflow to the penis is enhanced, leading to an erection. Sildenafil hasshown a response rate of around 80% in men with erectile dysfunction oforganic cause.

[0007] Since sildenafil has been developed, various compounds forinhibiting phosphodiesterase-5 have been reported. Among them,pyrazolopyrimidinone compounds of formula 1 (KR Pat. No. 99-49384) werereported having better potency than that of sildenafil, based on themechanism of inhibiting phosphodiesterase-5 and having betterselectivity over phosphodiesterase-6 distributed in retina andphosphodiesterase-3 distributed in heart to reduce the side effects.Further, the pyrazolopyrimidinone compounds of formula 1 were said to beimproved the solubility and the metabolism in the liver, which are veryimportant factor affecting the rate of the absorption when administeredorally.

[0008] The KR patent No. 99-49384 also disclosed a process for preparingthe pyrazolopyrimidinone compounds of formula 1, comprising the stepsof:

[0009] a) reacting chlorosulfonated alkoxy benzoic acid with a primaryamine to obtain sulfonamide-substituted benzoic acid;

[0010] b) reacting the obtained sulfonamide-substituted benzoic acidwith pyrazolamine in the presence of activating reagent of carboxylicgroup or coupling agent of carboxylic group with amine group to obtaincorresponding amide compound; and,

[0011] c) performing an intramolecular cyclization of the obtained amidecompound to obtain the pyrazolopyrimidinone compound of formula 1.

[0012] This reaction is represented in scheme 1.

[0013] However, the said process has several disadvantages. First, thereaction of the sulfonamide-substituted benzoic acid with pyrazolaminein the step b) requires the expensive coupling reagent or activationreagent such as trichloro benzoyl chloride and EEDQ(N-ethoxycarbonyl-2-ethoxy-1,3-dihydroquinoline). Second, the yield ofthe step a) in which the chlorosulfonated alkoxy bonzoic acid reactswith a primary amine to produce sulfonamide-substituted benzoic acid issomewhat low, and thus, reduces the total yield of the process.

[0014] Leading to the present invention, the intensive and thoroughresearch for efficiently preparing the pyrazolopyrimidinone compounduseful for the treatment of impotence, carried out by the presentinventors aiming to avoid the problems encountered in the prior arts,resulted in the finding that the pyrazolopyrimidinone compound can beprepared under mild condition in high yield, with high purity and in aeconomic manner by chlorosulfonation, amination with a primary amine andintramolecular cyclization of a pyrazolamide compound obtained by thereaction of alkoxy benzoic acid with pyrazolamine.

[0015] Therefore, it is an object of the present invention to provide aprocess for preparing pyrazolopyrimidinone derivatives of formula 1 andpharmaceutically acceptable salts thereof.

DISCLOSURE OF THE INVENTION

[0016] The present invention provides a process for preparingpyrazolopyrimidinone derivatives of formula 1 and pharmaceuticallyacceptable salts thereof.

[0017] Referring to scheme 2, the process according to the presentinvention comprises the steps of:

[0018] a) chlorosulfonating a pyrazolamide compound of formula 2 toobtain a chlorosulfonated compound of formula 3;

[0019] b) reacting the chlorosulfonated compound of formula 3 with aprimary amine to obtain a sulfonamide compound of formula 4; and,

[0020] c) performing an intramolecular cyclization of the sulfonamidecompound of formula 4 to produce the compound of formula 1.

[0021] Wherein,

[0022] R₁ represents hydrogen, C₁-C₆ alkyl, C₁-C₃ alkyl fluoride orC₃-C₆ cycloalkyl;

[0023] R₂ represents hydrogen, substituted or unsubstituted C₂-C₆ alkyl,C₁-C₃ alkyl fluoride or C₃-C₆ cycloalkyl;

[0024] R₃ represents substituted or unsubstituted C₁-C₆ alkyl, C₁-C₆alkyl fluoride, C₃-C₆ cycloalkyl, C₃-C₆ alkenyl or C₃-C₆ alkynyl; and,

[0025] R₄ represents substituted or unsubstituted C₁-C₁₀ alkyl,substituted or unsubstituted C₁-C₉ alkenyl, substituted or unsubstitutedC₃-C₆ cycloalkyl, substituted or unsubstituted benzene, or substitutedor unsubstituted heterocycle selected from the group consisting ofpyridine, isoxazole, thiazole, pyrimidine, indan, benzthiazole,pyrazole, thiadiazol, oxazole, piperidine, morphorine, imidazole,pyrrolidine, thienyl, triazole, pyrrole and furyl.

[0026] As a substituent of R₂, R₃ and R₄, C₁-C₁₀ alkyl, C₃-C₆cycloalkyl, halogen, C₁-C₆ alkyl fluoride, C₁-C₁₀ alkyloxy, substitutedor unsubstituted bezene, or substituted or unsubstituted heterocycleselected from the group consisting of pyridine, isoxazole, thiazole,pyrimidine, indan, benzthiazole, pyrazole, thiadiazole, oxazole,piperidine, morphorine, imidazole, pyrrolidine, thienyl, triazole,pyrrole, and furyl can be mentioned.

[0027] Preferably, R₁ represents C₁-C₃ alkyl; R₂ represents substitutedor unsubstituted C₂-C₆ alkyl; R₃ represents substituted or unsubstitutedC₂-C₆ alkyl; R₄ represents substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted C₃-C₆ cycloalkyl, substituted orunsubstituted bezene, substituted or unsubstituted pyridine, orsubstituted or unsubstituted pyrrole, wherein the substituent of R₂, R₃and R₄ is halogen, substituted or unsubstituted benzene, substituted orunsubstituted heterocycle selected from the group consisting ofpyridine, pyrrolidine, piperidine, pyrrole, and substituted orunsubstituted C₃-C₆ cycloalkyl.

[0028] More preferably, R₄ represents substituted C₁-C₆ alkyl, whereinthe substituent is pyrrolidine.

[0029] Particularly preferred are as follows:

[0030] (1) 5-[2-propoxy-5-(1-methyl-2-pyrrolidinylethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one;

[0031] (2) 5-[2-propoxy-5-(1-methyl-3-pyrrolidinylmethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one;and

[0032] (3) 5-[2-propoxy-5-(2-pyridylmethyl amidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one.

[0033] Hereinafter, a detailed description will be given of the methodof the present invention according to each step.

[0034] I. Chlorosulfonation Step (Step a)

[0035] 4-(2-alkoxy benzamido)-1-alkyl-3-alkyl-5-carbamoyl pyrazole offormula 2 is directly reacted with chlorosulfonic acid or reacted with amixture of chlorosulfonic acid and suitable amounts of thionyl chlorideat an appropriate temperature, 20° C. or lower, to prepare thechlorosulfonated compound of formula 3.

[0036] II. Sulfonamidization Step (Step b)

[0037] The obtained chlorosulfonated compound is reacted with a primaryamine in an appropriate solvent at suitable temperature, to produce thesulfonamide compound of formula 4.

[0038] The solvent which can be used in this reaction includes alcohol,dichloromethane and chloroform, but not limited thereto. The skilled inthe art would adapt an appropriate solvent in the consideration of thesolubility of the starting material, reaction condition, etc.

[0039] As a primary amine used, 2-(2-aminoethyl)-1-methylpyrrolidine,3-aminomethyl-1-methylpyrrolidine or 2-aminomethyl-pyridine can bepreferably mentioned. The amount of the primary amine used in thisreaction is no less than 2 equivalents based on the chlorosulfonatedcompound. Alternatively, when acid scavenger such as tertiary amine,which scavenging the acid generated during the reaction, is used, theprimary amine can be used in a stoichiometric quantity.

[0040] The reaction temperature of this reaction is preferably 20° C. orlower. The sulfonamide compound of formula 4 can be worked up from thereaction mixture and proceeded to the next reaction step c). Or step c)can be performed in situ by just adding a suitable base to the reactionmixture in situ without workup.

[0041] III. Intramolecular Cyclization Step (Step c)

[0042] Pyrazolopyrimidinone of formula 1 is prepared throughintramolecular cyclization of the sulfonamide compound of formula 4. Theintramolecular cyclization is carried out in the presence of a suitablebase at the appropriate temperature. For example, metal salts ofalcohol, metal salts of ammonia, amine, alkali or alkali earth metalhydrides, hydroxides, carbonates, bicarbonates, and bicyclic amidinessuch as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and DBN(1,5-diazabicyclo[4.3.0]non-5-ene) can be mentioned as a suitable base.

[0043] The solvent which can be used in the intramolecular cyclizationincludes alcohol such as methanol, ethanol, isopropanol and t-butanol;ether including tetrahydrofuran, dimethoxyethane and dioxane; aromatichydrocarbons, such as benzene, toluene, xylene, chloro benzene;acetonitrile, dimethylsulfoxide, dimethylformamide,N-methylpyrrolidin-2-one and pyridine.

[0044] The present invention provides the sulfonamide compound offormula 4 from step a) and step b) reaction in good yield and in highpurity. And as previously mentioned, the step c) can be performed insitu with the sulfonamide compound of formula 4 produced in the step b)in a one-pot reaction, thereby reducing the overall procedure of thereaction and effectuating the efficient synthesis ofpyrazolopyrimidinone compound of formula 1.

[0045] In particular, according to the preferred embodiment of thepresent invention, even though tertiary amine was used as a part ofsubstituent of R₄, the yield of the reaction was high.

[0046] The present invention also provides a method for preparingpharmaceutically acceptable salts of pyrazolopyrimidinone compound asrepresented in formula 1, wherein the pharmaceutically acceptable saltsof pyrazolopyrimidinone compound can be prepared by adding apharmaceutically acceptable free acid to the pyrazolopyrimidinonecompound of formula 1. Examples of a free acid include inorganic acids,for example, hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid and so on; and organic acids, for example, citric acid,acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid,gluconic acid, methanesulfonic acid, glycolic acid, succinic acid,p-toluenesulfonic acid, galacturonic acid, glutamic acid, or asparticacid.

[0047] A better understanding of the present invention may be obtainedin light of the following examples which are set forth to illustrate,but are not to be construed to limit the present invention.

EXAMPLE

[0048] Molecular structures of the present compounds were confirmed byinfrared spectrometry, ultraviolet spectrometry, nuclear magneticresonance spectrometry, mass spectrometry, and elemental analysis ofrepresentative compounds by comparing calculated values with observedvalues.

[0049] The pyrazolamide compound of formula 2, which is a startingmaterial of the present invention, can be obtained in high yield byreacting alkoxy benzoic acid with pyrazolamine as illustrated in thescheme 2.

Preparation Preparation of 4-[2-PropoxyBenzamido]-1-Methyl-3-Propyl-5-Carbamoyl Pyrazole

[0050] To a solution of 25 g of 2-propoxy benzoic acid dissolved indichloromethane, 66 g of thionyl chloride was added and stirred for 3hours under reflux. After reaction was completed, the solvent andexcessive thionyl chloride were distilled off under reduced pressure. Tothe residue was added 200 ml of dichloromethane (reaction solution 1).In another container, to 24 g of 1-methyl-3-propyl-4-amino-5-carbamoylpyrazole in dichloromethane was added 13.4 g of triethylamine and 100 mgof dimethylaminopyridine and then cooled to 0° C., to which saidreaction solution 1 was slowly added while maintaining the temperatureof the solution at 0° C., and then stirred for 1 hour. The reactionmixture was successively washed with water, saturated aqueous sodiumbicarbonate solution and brine. The organic layer was dried overanhydrous sodium sulfate and then filtered. The filtrate wasconcentrated under reduced pressure to obtain a crude product and thentriturated with hexane to give 39 g of the title compound.

[0051]¹H NMR (CDCl₃): 0.91(t,3H), 1.05(t,3H), 1.62(m,2H), 1.89(m,2H),2.52(t,2H), 4.06(s,3H), 4.18(t,2H), 5.57(br s,1H), 7.09(m,2H),7.52(m,1H), 7.73(br s,1H), 8.26(dd,1H), 9.45(br s,1H)

EXAMPLE 1A Preparation of 5-[2-Propoxy-5-(1-Methyl-2-PyrolidinylethylAmidosulfonyl)Phenyl]-1-Methyl-3-Propyl-1,6-Dihydro-7H-Pyrazolo(4,3-d)Pyrimidin-7-One(Step a) Preparation of4-[2-Propoxy-5-(Chlorosulfonyl)Benzamido]-1-Methyl-3-Propyl-5-CarbamoylPyrazole

[0052] To 23 ml of chlorosulfonic acid cooled to 0° C., 10 g of4-[2-propoxy benzamido]-1-methyl-3-propyl-5-carbamoyl pyrazole was addedand then stirred at room temperature for 2 hours. Reaction mixture wasadded to ice water of 0° C. and then stirred for 1 hour to obtain whitesolid, which was filtered and washed with water. The obtained whitesolid was dissolved in ethyl acetate. The solution was successivelywashed with water and brine. The organic layer was dried over anhydrousmagnesium sulfate and filtered. The filtrate was concentrated underreduced pressure to obtain a crude product and triturated with hexane togive 9.14 g of the title compound.

[0053]¹H NMR (CDCl₃): 0.92(t,3H), 1.08(t,3H), 1.62(m,2H), 1.97(m,2H),2.50(t, 2H), 4.04(s,3H), 4.32(t,2H), 5.63(br s,1H), 7.24(d,1H), 7.54(brs, 1H), 8.15(dd,1H), 8.93(d,1H), 9.17(br s,1H)

(Step 2) Preparation of 4-[2-Propoxy-5-(1-Methyl-2-PyrolidinylethylAmidosulfonyl)Benzamido]-1-Methyl-3-Propyl-5-Carbamoyl Pyrazole

[0054] To 9.14 g of 4-[2-propoxy-5-(chlorosulfonyl)benzamido]-1-methyl-3-propyl-5-carbamoyl pyrazole in dichloromethane, 5ml of 2-(2-aminoethyl)-1-methyl pyrrolidine was added at 0° C. andstirred for 1 hour at room temperature. After completion of reaction,the reaction solution was diluted with dichloromethane. The solution wassuccessively washed with saturated sodium bicarbonate solution, waterand brine. The organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure toproduce a crude product and triturated with a mixture of hexane:ethylacetate (10:1) to give 9.69 g of the pure title compound.

[0055]¹H NMR (CDCl₃): 0.90(t,3H), 1.06(t,3H), 1.59(m,2H), 1.70(m,6H),1.93(m, 2H), 2.15(m,1H), 2.29(s,3H), 2.39(m.1H), 2.49(t,2H), 3.04(m,3H),4.02(s,3H), 4.24(t,2H), 5.82(br s, 1H), 7.13 (d, 1H). 7.58 (br s, 1H),7.96 (dd, 1H), 8.67 (d, 1H), 9.26(br s,1H)

(Step 3) Preparation of 5-[2-Propoxy-5-(1-Methyl-2-PyrolidinylethylAmidosulfonyl)Phenyl]-1-Methyl-3-Propyl-1,6-Dihydro-7H-Pyrazolo(4,3-d)Pyrimidin-7-One

[0056] To a solution of 9.59 of4-[2-propoxy-5-(1-methyl-2-pyrolidinylethylamidosulfonyl)benzamido]-1-methyl-3-propyl-5-carbamoyl pyrazoledissolved in 192 ml of t-butanol, 4.02 g of potassium t-butoxide wasadded and then stirred for 8 hours under reflux. After completion ofreaction, the reaction solution was cooled to room temperature anddiluted with ethyl acetate. The solution was successively washed withwater and brine. The organic layer was dried over anhydrous magnesiumsulfate and filtered. The filtrate was vacuum-distilled to remove thesolvent. Column chromatography of the residue on silica gel gave 7 g ofthe pure title compound.

[0057]¹H NMR (CDCl₃): 0.99(t,3H), 1.15(t,3H), 1.56(m,4H), 1.79(m,4H),2.02(m,3H), 2.28(s,3H), 2.36(m,1H), 2.89(t,2H), 3.07(m,3H), 4.23(t,2H),4.24(s,3H), 7.11(d,1H), 7.92(dd,1H), 8.88 (d,1H)

EXAMPLE 1B Preparation of 5-[2-Propoxy-5-(1-Methyl-2-PyrolidinylethylAmidosulfonyl)Phenyl]-1-Methyl-3-Propyl-1,6-Dihydro-7H-Pyrazolo(4,3-d)Pyrimidin-7-One(Step 1) Preparation of4-[2-Propoxy-5-(Chlorosulfonyl)Benzamido]-1-Methyl-3-Propyl-5-CarbamoylPyrazole

[0058] To 32.8 ml of chlorosulfonic acid cooled to 0° C., 8.48 ml ofthionyl chloride and 20 g of 4-[2-propoxybenzamido]-1-methyl-3-propyl-5-carbamoyl pyrazole were successivelyadded dropwise and portionwise, and then stirred for 2 hours at roomtemperature. Reaction mixture was added to ice water of 0° C. After 1hour, the reaction mixture was extracted with ethyl acetate. The organicsolution was successively washed with water and brine. The organic layerwas dried over anhydrous magnesium sulfate and filtered. The filtratewas concentrated under reduced pressure to obtain a crude product andtriturated with a mixture of hexane:ethyl acetate (10:1) to give 23 g ofthe title compound.

[0059]¹H NMR(CDCl₃): 0.92(t,3H), 1.08(t,3H), 1.62(m,2H), 1.97(m,2H),2.50(t, 2H), 4.04(s,3H), 4.32(t,2H), 5.63(br s,1H), 7.24(d,1H), 7.54(brs, 1H), 8.15(dd,1H), 8.93(d,1H), 9.17(br s,1H).

(Steps 2 and 3) Preparation of5-[2-Propoxy-5-(1-Methyl-2-PyrolidinylethylAmidosulfonyl)Phenyl]-1-Methyl-3-Propyl-1,6-Dihydro-7H-Pyrazolo(4,3-d)Pyrimidin-7-One

[0060] To 20.8 g of 4-[2-propoxy-5-(chlorosulfonyl)benzamido]-1-methyl-3-propyl-5-carbamoyl pyrazole in ethanol, 11.3 ml of2-(2-aminoethyl)-1-methyl pyrrolidine was added at 0° C. and stirred for1 hour at room temperature. To this solution, 12 g of sodium ethoxidewas added and stirred for 5 hours under reflux. After completion ofreaction, the reaction solution was cooled to room temperature andadjusted to pH 9 by concentrated hydrochloric acid. The reactionsolution was diluted with dichloromethane. The solution was successivelywashed with water and brine. The organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was concentrated under reducedpressure to remove the solvent, which was then recrystallized withethanol to give 18.4 g of the pure title compound.

[0061]¹H NMR(CDCl₃): 0.99(t,3H), 1.15(t,3H), 1.56(m,4H), 1.79(m,4H),2.02(m,3H), 2.28(s,3H), 2.36(m,1H), 2.89(t,2H), 3.07(m,3H), 4.23(t,2H),4.24(s,3H), 7.11(d,1H), 7.92(dd,1H), 8.88 (d,1H).

EXAMPLE 2 Preparation of 5-[2-Propoxy-5-(1-Methyl-3-PyrolidinylmethylAmidosulfonyl)Phenyl]-1-Methyl-3-Propyl-1,6-Dihydro-7H-Pyrazolo(4,3-d)Pyrimidin-7-One(Step 1) Preparation of4-[2-Propoxy-5-(Chlorosulfonyl)Benzamido]-1-Methyl-3-Propyl-5-CarbamoylPyrazole

[0062] The title compound was produced in the same manner as in the step1 of the above example 1B.

(Step 2) Preparation of 4-[2-Propoxy-5-(1-Methyl-3-PyrrolidinylmethylAmidosulfonyl)Benzamido]-1-Methyl-3-Propyl-5-Carbamoyl Pyrazole

[0063] To 1.0 g of 4-[2-propoxy-5-(chlorosulfonyl)benzamido]-1-methyl-3-propyl-5-carbamoyl pyrazole in dichloromethane,516 mg of 3-aminomethyl-1-methyl pyrrolidine was added at 0° C. andstirred for 1 hour at room temperature. After completion of reaction,the reaction solution was diluted with dichloromethane. The solution wassuccessively washed with saturated sodium bicarbonate solution, waterand brine. The organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure to give acrude product and triturated with hexane to give 825 mg of the puretitle compound.

[0064]¹H NMR(CDCl₃): 0.91(t,3H), 1.06(t,3H), 1.60(m,3H), 1.99(m,3H),2.34(s, 3H), 2.40(m,6H), 2.85(m,1H), 2.94(d0.2H), 4.03(s,3H),4.24(t,2H), 5.82(br s,1H), 7.13(d,1H). 7.58(br s,1H), 7.99(dd,1H),8.88(d,1H), 9.29(br s,1H).

(Step 3) Preparation of 5-[2-Propoxy-5-(1-Methyl-3-PyrrolidinylmethylAmidosulfonyl)phenyl]-1-Methyl-3-Propyl-1,6-Dihydro-7H-Pyrazolo(4,3-d)Pyrimidin-7-One

[0065] To a solution of 825 mg of4-[2-propoxy-5-(1-methyl-3-pyrrolidinylmethyl amidosulfonyl)benzamido]-1-methyl-3-propyl-5-carbamoyl pyrazole dissolved in 10 ml oft-butanol, 213 mg of potassium t-butoxide was added and then stirred for8 hours under reflux. After completion of reaction, the reactionsolution was cooled to room temperature and diluted withdichloromethane. The solution was successively washed with water andbrine. The organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure to removethe solvent. Column chromatography of the crude product on silica gelgave 719 mg of the pure title compound.

[0066]¹H NMR(CDCl₃): 1.00(t,3H), 1.16(t,3H), 1.60(m,1H), 1.82(m,2H),2.02(m,3H), 2.38(s,3H), 2.50(m,4H), 2.90(t,2H), 3.01(d,2H), 4.23(t,2H),4.25(s,3H), 7.12(d,1H), 7.94(dd,1H), 8.88 (d,1H).

EXAMPLE 3 Preparation of 5-[2-Propoxy-5-(2-PyridylmethylAmidosulfonyl)Phenyl]-1-Methyl-3-Propyl-1,6-Dihydro-7H-Pyrazolo(4,3-d)Pyrimidin-7-One(Step 1) Preparation of4-[2-Propoxy-5-(Chlorosulfonyl)benzamido]-1-Methyl-3-Propyl-5-CarbamoylPyrazole

[0067] The title compound was prepared in the same manner as in the step1 of the above example 1B.

(Step 2) Preparation of 4-[2-Propoxy-5-(2-PyridylmethylAmidosulfonyl)Benzamido]-1-Methyl-3-Propyl-5-Carbamoyl Pyrazole

[0068] To 1.0 g of 4-[2-propoxy-5-(chlorosulfonyl)benzamido]-1-methyl-3-propyl-5-carbamoyl pyrazole in dichloromethane,0.47 ml of 2-aminomethyl-pyridine was added at 0° C. and stirred for 1hour at room temperature. After completion of reaction, the reactionsolution was diluted with dichloromethane. The solution was successivelywashed with saturated sodium bicarbonate solution, water and brine. Theorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure to furnish a crudeproduct and triturated with hexane to give 955 mg of the pure titlecompound.

[0069]¹H NMR(CDCl₃): 0.90(t,3H), 1.05(t,3H), 1.59(m,2H), 1.90(m,2H),2.49(t, 2H), 2.65(br s,1H), 4.02(s,3H), 4.25(t,2H), 4.28(d,2H), 5.79(brs,1H), 6.28(t,1H), 7.09(d,1H). 7.26(d,1H), 7.16(m,1H), 7.61(m,1H),7.99(dd,1H), 8.42(d,1H), 8.69(d,1H), 9.22(br s,1H).

(Step 3) Preparation of 5-[2-Propoxy-5-(2-PyridylmethylAmidosulfonyl)Phenyl]-1-Methyl-3-Propyl-1,6-Dihydro-7H-Pyrazolo(4,3-d)Pyrimidin-7-One

[0070] To a solution of 955 mg of 4-[2-propoxy-5-(2-pyridylmethylamidosulfonyl)benzamido]-1-methyl-3-propyl-5-carbamoyl pyrazoledissolved in 12 ml of t-butanol, 244 mg of potassium t-butoxide wasadded and then stirred for 8 hours under reflux. After completion ofreaction, the reaction solution was cooled to room temperature anddiluted with ethyl acetate. The solution was successively washed withwater and brine. The organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated under reducedpressure to remove the solvent. The reidue was column chromatographed onsilica gel to give 821 mg of the pure title compound.

[0071]¹H NMR(CDCl₃): 1.02(t,3H), 1.15(t,3H), 1.85(m,2H), 2.04(m,2H),2.93(t,2H), 4.21(t,2H), 4.26(s,3H), 4.41(d,2H), 6.30(t,1H), 7.09(d,1H),7.30(m,1H), 7.39(d,1H), 7.77(m,1H), 7.96(dd,1H), 8.45(d,1H), 8.86(d,1H),10.82(br s,1H).

[0072] According to the present invention, pyrazolopyrimidinonederivatives of formula 1 can be prepared in high yield with high purity.In addition, the inexpensive reagents can be used such that they can beprepared in an economic manner.

[0073] The present invention has been described in an illustrativemanner, and it is to be understood that the terminology used is intendedto be in the nature of description rather than of limitation. Manymodifications and variations of the present invention are possible inlight of the above teachings. Therefore, it is to be understood thatwithin the scope of the appended claims, the invention may be practicedotherwise than as specifically described.

What is claimed is:
 1. A method for preparing pyrazolopyrimidinonederivatives of formula 1, as represented in the following scheme 2,comprising the following steps of: a) chlorosulfonating a pyrazolamidecompound of formula 2 to obtain a chlorosulfonated compound of formula3; b) reacting the chlorosulfonated compound of formula 3 with a primaryamine to obtain a sulfonamide compound of formula 4; and, c) performingan intramolecular cyclization of the sulfonamide compound of formula 4to produce the compound of formula
 1.


2. The method according to claim 1, wherein R₁ represents hydrogen;C₁-C₆ alkyl; C₁-C₃ alkyl fluoride; or C₃-C₆ cycloalkyl, R₂ representshydrogen; substituted or unsubstituted C₂-C₆ alkyl; C₁-C₃ alkylfluoride; or C₃-C₆ cycloalkyl, R₃ represents substituted orunsubstituted C₁-C₆ alkyl; C₁-C₆ alkyl fluoride; C₃-C₆ cycloalkyl; C₃-C₆alkenyl; or C₃-C₆ alkynyl, and R₄ represents substituted orunsubstituted C₁-C₁₀ alkyl; substituted or unsubstituted C₁-C₉ alkenyl;substituted or unsubstituted C₃-C₆ cycloalkyl; substituted orunsubstituted bezene; or substituted or unsubstituted heterocycleselected from the group consisting of pyridine, isoxazole, thiazole,pyrimidine, indan, benzthiazole, pyrazole, thiadiazol, oxazole,piperidine, morphorine, imidazole, pyrrolidine, thienyl, triazole,pyrrole and furyl, in which, substituents usable for R₂, R₃ and R₄comprises C₁-C₁₀ alkyl; C₃-C₆ cycloalkyl; halogen; C₁-C₆ alkyl fluoride;C₁-C₁₀ alkyloxy; substituted or unsubstituted bezene; or substituted orunsubstituted heterocycle selected from the group consisting ofpyridine, isoxazole, thiazole, pyrimidine, indan, benzthiazole,pyrazole, thiadiazole, oxazole, piperidine, morphorine, imidazole,pyrrolidine, thienyl, triazole, pyrrole, and furyl.
 3. The methodaccording to claim 1, wherein R₁ represents C₁-C₃ alkyl, R₂ representssubstituted or unsubstituted C₂-C₆ alkyl, R₃ represents substituted orunsubstituted C₂-C₆ alkyl, and R₄ represents substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted bezene, substituted orunsubstituted pyridine, or substituted or unsubstituted pyrrole, inwhich, substituents usable for R₂, R₃ and R₄ comprises halogen,substituted or unsubstituted benzene, substituted or unsubstitutedheterocycle selected from the group consisting of pyridine, pyrrolidine,piperidine, pyrrole, and substituted or unsubstituted C₃-C₆ cycloalkyl.4. The method according to claim 1, wherein said derivative of formula 1is selected from the group consisting of5-[2-propoxy-5-(1-methyl-2-pyrrolidinylethylamidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one,5-[2-propoxy-5-(1-methyl-3-pyrrolidinylmethyl amidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one, and 5-[2-propoxy-5-(2-pyridylmethyl amidosulfonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one.5. The method according to claim 1, wherein said step a) is carried outat about 20° C. or lower.
 6. The method according to claim 1, whereinsaid step b) is carried out at about 20° C. or lower.
 7. The methodaccording to claim 1, wherein said step c) is performed in the presenceof a solvent selected from the group consisting of alcohol,dichloromethane and chloroform.
 8. The method according to claim 1,wherein said step c) is performed in the presence of a solvent selectedfrom the group consisting of alcohols, ethers, aromatic hydrocarbons,acetonitrile, dimetylsulfoxide, dimethylformamide,N-methylpyrrolidin-2-one and pyridine.
 9. The method according to claim1, wherein the said c) is performed in the presence of a base selectedfrom the group consisting of metal salts of alcohols, metal salts ofammonia, amines, alkali or alkali earth metal hydrides, hydroxides,carbonates, bicarbonates, and bicyclic amidines such as DBU(1,8-diazabicyclo[5.4.0]undec-7-ene) and DBN(1,5-diazabicyclo[4.3.0]non-5-ene).
 10. A method for preparing salts ofpyrazolopyrimidinone derivatives of formula 1 by reactingpyrazolopyrimidinone compounds with a free acid.
 11. The methodaccording to claim 10, wherein said free acid is selected from the groupconsisting of hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, citric acid, acetic acid, lactic acid, tartaric acid,maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, glycolicacid, succinic acid, p-toluenesulfonic acid, galacturonic acid, glutamicacid and aspartic acid.